Interleukin-1 receptor antagonist (IL-1ra) exists in two forms which are produced through alternate start sites and internal splicing of a single gene. Secretory IL-1ra (sIL-1ra) has a leader sequence, is secreted, is a significant product of monocytes, and probably functions as an antagonist of extracellular IL-1. Intracellular IL-1ra (icIL-1ra) lacks a leader sequence, probably remains predominantly intracellular, is a significant product of epithelial cells, and may function as an antagonist of intracellular IL-1. The hypothesis to be examined in these studies is that monocyte/macrophage cells produce both sIL-1ra and icIL-1ra. It is further hypothesized production of both forms of IL-1ra by these cells is regulated separately. Four specific aims will be pursued: 1) to accurately quantitate sIL-1ra and icIL-1ra mRNA utilizing quantitative PCR techniques, 2)to accurately quantitate sIL-1ra and icIL-1ra protein concentrations utilizing a sensitive and specific ELISA, 3) to examine the differential regulation of sIL-1ra and icIL-1ra mRNA and protein production in different cell types, and 4) to examine the potential biologic role of icIL-1ra. The results of these studies should clarify the possible in vivo relevance of sIL-1ra and icIL-1ra in rheumatoid arthritis and in other chronic inflammatory diseases.